PTPN2 Deficiency Enhances Programmed T Cell Expansion and Survival Capacity of Activated T Cells

• DOI: 10.1016/j.celrep.2020.107957
• Publication Date: 2020-07-28T14:47:43Z
• Authors: Markus Flosbach; Susanne G. Oberle; Stefanie Scherer; Jana Zecha; Madlaina von Hoes...; Florian Wiede; Vijaykumar Chennu...; Jolie G. Cullen; Markus List; Josch K. Pauling; Jan Baumbach; Bernhard Kuster; Tony Tiganis; Dietmar Zehn
• Keywords: Male; adoptive T cell transfer; QH301-705.5; T-Lymphocytes; Receptors, Antigen, T-Cell; 610; T cell memory; Cell Communication; Lymphocyte Activation; Immunotherapy, Adoptive; Article; Mice; 03 medical and health sciences; ddc:630; Animals; Biology (General); Phosphorylation; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 2; 0303 health sciences; programmed T cell expansion; ddc:; 3. Good health; Mice, Inbred C57BL; Protein tyrosine phosphatase non‑receptor type 2 (PTPN2); Animals; Carrier Proteins/metabolism; Cell Communication; Cytokines/metabolism; Female; Immunotherapy, Adoptive/methods; Lymphocyte Activation/genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism; Receptors, Antigen, T-Cell/metabolism; Signal Transduction; T-Lymphocytes/metabolism; GWAS; Protein tyrosine phosphatase non‑receptor type 2 (PTPN2); T cell memory; adoptive T cell transfer; autoimmunity; effector T cells; immunotherapy; phosphoproteome; programmed T cell expansion; single point mutation; Cytokines; Female; immunotherapy; Carrier Proteins; effector T cells; Signal Transduction

Manipulating molecules that impact T cell receptor (TCR) or cytokine signaling, such as the protein tyrosine phosphatase non-receptor type 2 (PTPN2), has significant potential for advancing T cell-based immunotherapies. Nonetheless, it remains unclear how PTPN2 impacts the activation, survival, and memory formation of T cells. We find that PTPN2 deficiency renders cells in vivo and in vitro less dependent on survival-promoting cytokines, such as interleukin (IL)-2 and IL-15. Remarkably, briefly ex vivo-activated PTPN2-deficient T cells accumulate in 3- to 11-fold higher numbers following transfer into unmanipulated, antigen-free mice. Moreover, the absence of PTPN2 augments the survival of short-lived effector T cells and allows them to robustly re-expand upon secondary challenge. Importantly, we find no evidence for impaired effector function or memory formation. Mechanistically, PTPN2 deficiency causes broad changes in the expression and phosphorylation of T cell expansion and survival-associated proteins. Altogether, our data underline the therapeutic potential of targeting PTPN2 in T cell-based therapies to augment the number and survival capacity of antigen-specific T cells.